Aspartame

The artificial sweetener aspartame (E951), marketed as NutraSweet, AminoSweet, Equal and Canderel, has been the subject of constant controversy since its initial approval by the U.S. Food and Drug Administration (FDA) in 1974. Critics point to the conflicts of interest that marred the FDA's approval of aspartame, the shoddy industry-funded research supporting its safety, and point to independent research that shows numerous health risks associated with aspartame.

By 1998, aspartame products were the cause of 80% of complaints to the FDA about food additives. The complaints included headache, dizziness, change in mood, vomiting or nausea, abdominal pain and cramps, change in vision, diarrhea, seizures/convulsions, memory loss, and fatigue. Many studies have linked aspartame with a variety of conditions, including cancer. The cancer link was confirmed in 2011.

Aspartame was found to be safe for human consumption by more than ninety countries, however the regulatory agencies have accepted the company-sponsored research without ever having done independent confirmatory studies.

Genetic modification
Aspartame is manufactured from phenylalanine produced by a genetically modified (GM) strain of E. coli, a bacterium normally found in the bowel.

Decomposition
Aspartame in bottled liquids breaks down after six to eight weeks of shelf life. Aspartame's major decomposition products are diketopiperazine, aspartyl-phenylalanine, and phenylalanine, as well as methanol. At 180ºC, aspartame undergoes decomposition to form a diketopiperazine derivative (DKP). Upon ingestion, aspartame breaks down into aspartic acid, phenylalanine, methanol (a nerve poison), and further breakdown products including formaldehyde, known to be a human carcinogen, formic acid (also a nerve poison), and DKP (diketopiperazine), named as a carcinogen in a 2008 study.

History of approval and safety
The controversy over aspartame safety originated in irregularities in the aspartame approval process during the 1970s and early 1980s, including allegations of conflicts of interest and claims that aspartame producer G.D. Searle, a Monsanto subsidiary, had withheld safety data. In 1996, the controversy reached a wider audience with a 60 Minutes report on concerns that aspartame could cause brain tumors in humans.

Approval in the United States
Aspartame was originally approved for use in dry foods in 1974 by then FDA Commissioner Alexander Schmidt after review by the FDA's Center for Food Safety and Applied Nutrition. Searle had submitted 168 studies on aspartame, including seven animal studies that were considered crucial by the FDA. Soon afterwards, John Olney, a professor of psychiatry and prominent critic of monosodium glutamate, along with James Turner, a public-interest lawyer and author of an anti-food-additive book, filed a petition for a public hearing, citing safety concerns. Schmidt agreed, pending an investigation into alleged improprieties in safety studies for aspartame and several drugs. In December 1975, the FDA placed a stay on the aspartame approval, preventing Searle from marketing aspartame.

Fraud
In 1976, the FDA notified then-U.S. attorney for Chicago, Sam Skinner, of the ongoing investigation of Searle, and in January 1977, formally requested that a grand jury be convened to investigate whether indictments should be filed against Searle for knowingly misrepresenting findings and "concealing material facts and making false statements" in aspartame safety tests (the first time in the FDA's history that they request a criminal investigation of a manufacturer). The U.S. Department of Justice instituted grand jury proceedings against Searle for fraud, but in February, 1977, Searle's law firm, Sidley & Austin, offered Skinner a job, which he accepted, recusing himself from the case. Despite complaints and urging from DOJ in Washington, neither the interim US attorney for Chicago, William Conlon, nor Skinner's successor, Thomas Sullivan, convened a grand jury, allowing the statute of limitations to expire. In December, 1977, Sullivan ordered the case dropped for lack of evidence, and Conlon was later also hired by Searle's law firm.

In 1986, a 110-page report by Senator Howard Metzenbaum alleged that the Chicago prosecutors "froze" the investigation so that the statute of limitations would run out.

In 1977 and 1978, an FDA task force and a panel of academic pathologists reviewed 15 aspartame studies by Searle, and concluded that, although minor inconsistencies were found, they would not have affected the studies' conclusions. This conclusion was reached despite the testimony of Dr. M. Adrian Gross, a former senior FDA toxicologist, who stated that Searle's studies were largely unreliable and that least one of the studies has established beyond any reasonable doubt that aspartame is capable of inducing brain tumors in experimental animals, and that by allowing aspartame to be placed on the market, the FDA has violated the Delaney Amendment, which makes it illegal for any residues of cancer-causing chemicals to be permitted in foods. In 1980, a Public Board of Inquiry (PBOI) found Searle's test results "bizarre" and, deciding that further study was needed on a postulated connection between aspartame and brain tumours, revoked approval of aspartame. Dr. Gross, the chief scientist on the FDA task force, told the CBS Nightly News staff in January, 1984, that Searle made "deliberate decisions" to cloak the toxic effects of aspartame. "They took great pains to camouflage these shortcomings of the study, filter and just present to the FDA what they wished the FDA to know. And they did other terrible things. For instance, animals would develop tumors while they were under study — well, G.D. Searle would remove these tumors from the animals," surgically masking the cancerous effects of aspartame.

Rumsfeld gets aspartame approved
Donald Rumsfeld, then president of G. D. Searle & Company (later sold to Monsanto), makers of NutraSweet, and simultaneously part of Ronald Reagan's transition team, vowed to "call in his markers" to get aspartame approved. Dr Arthur Hull Hayes was appointed as Commissioner of the FDA the day after Reagan's inauguration. In 1981, Hayes sought advice on aspartame's ban from a panel of FDA scientists and a lawyer. It soon became clear that the panel would uphold the ban by a 3-2 decision, but Hull then installed a sixth member on the commission, and the vote became deadlocked. He then personally broke the tie in aspartame's favor. Hayes justified his approval by citing an Ajinomoto-funded 1981 Japanese brain tumor study.

Several objections followed, but all were denied. Following aspartame's approval, Searle, which had been floundering financially in the late 1970s and early 1980s, saw its profits soar. In November 1983, Hayes left the FDA under a cloud and joined Burson-Marsteller, chief public relations firm for both Monsanto and GD Searle, as a senior medical advisor. The appointment was widely seen as a reward for his approval of aspartame.

GAO investigation
Because of the approval controversy, Senator Howard M. Metzenbaum requested an investigation by the U.S. Government Accountability Office (GAO) of aspartame's approval. In 1987, the GAO reported that protocol had been followed and provided a timeline of events in the approval process. At that time, of 67 scientists who responded to a questionnaire, 12 had major concerns about Aspartame's safety, 26 were somewhat concerned but generally confident in Aspartame safety, and 29 were very confident in Aspartame safety.

In 1987, the U.S. Government Accountability Office concluded that the FDA had addressed the safety issues raised internally and by outside scientists and concerned citizens, but that it did not have the expertise to evaluate the adequacy of the FDA's resolution of issues. The GAO report stated that ongoing research into aspartame, and monitoring of adverse reactions, should provide the FDA with a basis for determining what future actions, if any, are needed on aspartame.

Approval outside the US
Following the FDA's lead, food additive safety evaluations by many countries have led to approval of aspartame, citing the general lack of adverse effects following consumption in reasonable quantities reported by industry-funded research. Food safety authorities worldwide have set acceptable daily intake (ADI) values for aspartame at 40 mg/kg of body weight. The FDA has set its ADI for aspartame at 50 mg/kg.

Government action and voluntary withdrawals
In New Zealand in 2007, a petition to New Zealand parliament's health select committee called for restrictions on aspartame, based on the case of Abby Cormack, who chewed four packets of sugar-free gum a day and drank large quantities of diet soft drink, reported dizziness, tingling, insomnia, paranoia and other problems which she said ended when she quit aspartame. The committee did not agree to the petitioners' request, but in a minority report, the Green Party called for warning labels to highlight aspartame's "potential adverse effects".

In 2007, the Indonesian government considered banning Aspartame. In the Philippines, the small political party Alliance for Rural Concerns introduced House Bill 4747 in 2008 with the aim of having aspartame banned from the food supply. The US state of New Mexico introduced a bill to ban aspartame in 2007,  and Hawaiian legislators signed a 2009 resolution asking the FDA to rescind approval. In March 2009, the California OEHHA identified aspartame as a chemical for consultation by its Carcinogen Identification Committee, in accordance with California Proposition 65 (1986).

In 2007, the UK supermarket chains Sainsbury's, M&S, and Wal-Mart subsidiary Asda, announced that they would no longer use aspartame in their own label products.

In April 2009, Ajinomoto Sweeteners Europe, the world's largest manufacturer of aspartame, responded to Asda's "No Nasties" campaign, which removed aspartame from the store's own-brand foods, by filing a complaint of malicious falsehood against Asda in the English courts. In July 2009, Asda won the legal case after the trial judge construed the 'no nasties' labelling to "not mean that aspartame was potentially harmful or unhealthy", though it might be appealed.

In 2009, the South African retailer Woolworths announced it was removing aspartame from its own-brand foods.

In 2009, the education authorities in the Canadian state of British Columbia banned all sweeteners, including aspartame, from schools. Associated press articles made particular mention of aspartame.

In 2010, the British Food Standards Agency launched an investigation into aspartame amid claims that some people experience side-effects after consuming the substance. Results of the study are due in early 2011.

In May 2011, the European Food Safety Authority (EFSA) accepted a request from the European Commission for the re-evaluation of the safety of aspartame in 2012.

Consumption
A 12 ounce can of diet soda contains 180 mg of aspartame, and one liter of aspartame-sweetened soda contains 600 mg aspartame. U.S. diet beverage consumers average approximately 200 mg of daily aspartame consumption. For a 75 kg adult, it takes approximately 21 cans of diet soda to consume the 3,750 mg of aspartame that would surpass the FDA's 50 milligrams per kilogram of bodyweight ADI of aspartame.

Introduction
While numerous scientific studies, most of which were funded by industry, found no adverse effects of aspartame ingestion, several scientists have recommended further research into postulated connections between aspartame and an increase in malignant brain tumors from 1982 to 1992 and in lymphoma.

In 2006, the US National Cancer Institute concluded in a study of over 470,000 men and women aged 50 to 69 that there was no statistically significant link between aspartame consumption and leukemias, lymphomas or brain tumors. The study compared how much of 4 types of aspartame-sweetened beverages the subjects said they had drunk in 1995 or 1996 to how likely they were to have developed these cancers during the following five years. This conclusion was questioned in letters to the journal's editors, which pointed out that the study did not consider non-beverage consumption of aspartame, did not estimate the subjects' long-term use of aspartame, and did not include any subjects who had consumed aspartame since childhood (as the subjects were all over 49 and aspartame beverages had only been on the market for 15 years). The letters concluded that the study design was inappropriate to test the stated hypothesis.

A 2007 study looked at aspartame and the genetics of cancer, and found that aspartame increased gene expressions in key oncogenes concerning all the investigated genes, especially in organs with a high proliferation rate (lymphoreticular organs, bone-marrow and kidney), and concluded that aspartame has a biological effect, even at the recommended daily maximum dose.

A 2010 study found that aspartame induced dose dependent chromosome aberrations "at all concentrations".

Ramazzini Foundation studies
In a series of studies, the respected European Ramazzini Foundation of Oncology and Environmental Sciences (ERF) reported a dose-independent, statistically significant increase in several malignancies of rats, concluding that aspartame is a potential carcinogen at normal dietary doses.

Exposures to aspartame continued until the animals' natural deaths, with the oldest rats living about 2.75–3.0 years. In the postnatal lifetime exposure study, aspartame caused mainly leukemias and lymphomas in males and females, peripheral nerve schwannomas in males, and possibly increases in total malignant tumors, kidney tumors, and brain tumors. The prenatal lifetime study showed increased incidences of lymphomas/leukemias in males and females, mammary gland cancers in females, and total tumor-bearing males.

The FDA requested study data from the Foundation, but in keeping with their policies, the data was not released. Therefore the FDA released a statement rejecting the findings, but stated that additional insight on the study findings could be provided by an internationally-sponsored pathology working group examination of appropriate tissue slides from the study.

Despite the rejection of the Ramazzini Foundation's findings, professor emeritus Samuel S. Epstein in 2009 called on the FDA to "promptly ban the continued use of aspartame" because of the Foundation's studies, inter alia. Several other scientists support the most recent ERF study. Two scientists referred to the newer study in their comments regarding the potential risks to workers who produce aspartame and are exposed to it under long-term conditions. They proposed that the FDA "should consider sponsoring a prospective epidemiologic study of aspartame workers."

In an open letter in June 2007 to the FDA, 11 doctors and PhDs argued that letting the animals live into old age —one of the most controversial aspects of the Italian studies— more accurately mimics how aspartame might affect people throughout their lifetimes. More studies, they say, should be done the same way. One of the signatories said that the Ramazzini studies "are the future".

In 2008, a study by the National Institute of Environmental Health Sciences endorsed the Ramazzini methodology, saying that extending animal bioassays beyond 2 years and beginning exposure in utero provides more reliable and appropriate indicators of human risk.

Morando Soffritti of the Ramazzini Foundation rejected the criticisms levelled at the ERF studies by Bernadene Magnuson, a reviewer paid by the aspartame industry, who exonerated the chemical in a controversial 2007 review (see below).

In 2011, the Ramazzini Foundation again linked aspartame to cancer. The new study looked at the effect of giving aspartame to mice. They were exposed to aspartame starting before their births (at 12 days of gestation) and lasting until their deaths. At that time, autopsies revealed a significantly increased risk of liver and lung cancer. According to the study in the American Journal of Industrial Medicine: "The results of the present study confirm that [aspartame] is a carcinogenic agent in multiple sites in rodents, and that this effect is induced in two species, rats (males and females) and mice (males)."

Industry-funded studies
In 2007, a review study was published by a panel of experts, declaring aspartame to be "very safe". The panel was chosen by the Burdock Group, a consulting firm serving the food, dietary supplement, and cosmetics industries, which was in turn hired by Ajinomoto, the world's largest aspartame manufacturer. Michael F. Jacobson, executive director of the consumer group Center for Science in the Public Interest (CSPI), said that the study was "totally unreliable" and that some members of the expert panel were "longstanding industry consultants". He also observed that the panel was highly accepting of studies finding aspartame safe, but highly critical of those linking aspartame to possible health risks. The panel coordinator responded that panel members were not told the name of the company funding the study until the study was submitted for publication in a peer-reviewed journal.

Critics ask whether the review has any credibility given that the authors have done paid work for Monsanto, several authors have official positions in trade and research associations funded by Monsanto, Ajinomoto, Coca Cola, and PepsiCo, several authors work for corporate advocacy groups, one of which called aspartame toxicity a 'nonissue' before the review was undertaken, and one author who consults for companies that sell aspartame and in the past has said that aspartame is safe. The chief scientist behind the review, Bernadene Magnuson, is a consultant to the aspartame and soft drink industry, and has travelled the world, funded by companies like Coca-Cola, to give reassuring lectures on the safety of aspartame.

A 2005 report in The Guardian stated that a 1996 review of aspartame research found that every single industry-funded study found aspartame safe, but 92% of independent studies identified one or more problems with its safety. The article referred to Ralph G. Walton, a professor of clinical psychiatry at Northeastern Ohio Universities Colleges of Medicine and Pharmacy, who states that industry funding may have affected the conclusions of aspartame-related research. Walton states that researchers with ties to industry find no safety problems, while many of those without ties to aspartame find toxicities.

Also in 2005, the British Medical Journal published a letter that noted that "the glaring disparity in results from industry funded and independently funded research is clearly of considerable concern."

Aspartame disease
H.J. Roberts, MD, coined the term "aspartame disease" in a book filled with over 1,000 pages of information about the negative health consequences of ingesting aspartame. Dr. Roberts reports that by 1998, aspartame products were the cause of 80% of complaints to the FDA about food additives. Some of these symptoms include headache, dizziness, change in mood, vomiting or nausea, abdominal pain and cramps, change in vision, diarrhea, seizures/convulsions, memory loss, and fatigue. Along with these symptoms, links to aspartame are made for fibromyalgia symptoms, spasms, shooting pains, numbness in your legs, cramps, tinnitus, joint pain, unexplainable depression, anxiety attacks, slurred speech, blurred vision, multiple sclerosis, systemic  lupus, and various cancers.

Methanol and formaldehyde
Approximately 10% of aspartame (by mass) is broken down into methanol in the small intestine. Most of the methanol is absorbed and quickly converted into formaldehyde, known to be a human carcinogen, and then to formic acid. A study funded by the NutraSweet Company found that the metabolism of aspartame does not damage the body because: (a) the quantity of methanol produced is too small to disrupt normal physiological processes; (b) methanol and formaldehyde are natural by-products of human metabolism and are safely processed by various enzymes; (c) there is more methanol in some natural fruit juices and alcoholic beverages than is derived from aspartame ingestion; and (d) even large doses of pure methanol have been shown in non-human primate studies to lead to ample accumulation of formic acid (as formate), while no formaldehyde was detected.

However, in experiments on rodents given radiolabeled aspartame, formaldehyde-labeled adducts to protein and DNA accumulated in the brain, liver, kidneys and other tissues after ingestion of either 20 mg/kg or 200 mg/kg of aspartame. However, according to a study funded by NutraSweet, these scientists were not directly measuring formaldehyde, but simply measuring levels of some by-product of the methanol from aspartame.

Dr. Kenneth E. McMartin, a methanol expert and professor of pharmacology, toxicology and neuroscience at the Louisiana State University Medical Center, said he believed that it was unlikely that someone could consume enough aspartame to let harmful levels of formaldehyde build up in the body.

Aspartylphenylalanine diketopiperazine
Aspartylphenylalanine diketopiperazine, a type of diketopiperazine (DKP), is created in products as aspartame breaks down over time. For example, researchers found that 6 months after aspartame was put into carbonated beverages, 25% of the aspartame had been converted to DKP.

Concern among some scientists has been expressed that this form of DKP would undergo a nitrosation process in the stomach producing a type of chemical that could cause brain tumors. However, a study funded by the NutraSweet Company found that the nitrosation of aspartame or the DKP in the stomach likely does not produce chemicals that cause brain tumors. In addition, only a minuscule amount of the nitrosated chemical can be produced. There are very few human studies on the effects of this form of DKP. However, a (one-day) exposure study showed that the DKP was tolerated without adverse effects.

Premature birth
A 2010 study of 59,334 pregnant Danish women showed that those having 1 or more servings of artificially sweetened drinks a day were found to be at a 38 per cent increased risk of pre-term delivery. Consumption of 4 or more servings a day was associated with an increased risk of 78 per cent. The conclusion was that daily intake of artificially sweetened soft drinks may increase the risk of preterm delivery. Length of gestation may be affected by exposure to methanol, a known nerve toxin, which can be metabolised in the body to form formic acid (another nerve toxin), as well as formaldehyde (which is what is used to preserve dead bodies). These are all constituents of aspartame (the most ubiquitous artificial sweetener).

Insulin resistance
A 2007 study, published in Diabetes Care, that measured blood levels of insulin, found that aspartame causes a spike in insulin level after consumption, inducing a similar rise in glucose and insulin levels at baseline to the sucrose meal. This could lead to insulin resistance and possibly type II diabetes.

A 2011 study showed that heavy aspartame exposure could directly contribute to increased blood glucose levels, and thus contribute to the associations observed between diet soda consumption and the risk of diabetes in humans.

Vestibular and cochlear toxicity
Aspartame may have idiosyncratic toxic effects for some people in the areas of vestibular and cochlear functioning. Such cases present with a history of nausea and headache, progressively getting worse with time and eventually involving vomiting, vertigo (dizziness), and ataxia (clumsiness, loss of co-ordination). Some cases also involve tinnitus (ringing in the ears) and high frequency hearing loss. Symptoms are reversible on cessation of consumption.

Phenylalanine
Fifty percent of aspartame by mass is broken down into phenylalanine. Some studies show effects on neurotransmitter levels in the brain or changes in seizure thresholds. Adverse effects of phenylalanine on fetuses have been observed only when blood phenylalanine levels remain at high levels as opposed to spiking occasionally.

A 1987 study found that consumption of dietary phenylalanine in the usual way, as a constituent of protein, does not elevate brain phenylalanine levels because the protein elevates plasma levels of the other large neutral amino acids (LNAA) (valine, leucine, isoleucine, tryptophan, tyrosine) more than those of phenylalanine. In contrast, consumption of phenylalanine in the form of aspartame elevates plasma phenylalanine levels without elevating those of the other LNAA, and this causes marked elevations in the plasma phenylalanine ratio (the ratio of the plasma phenylalanine concentration to the summed concentrations of the other LNAA). The study noted that aspartame is "probably the only phenylalanine-containing food that man has ever eaten which elevates this ratio". An elevation in the plasma phenylalanine ratio causes a parallel rise in brain phenylalanine levels and also tends to reduce the corresponding ratios for the other LNAA, thus decreasing their brain uptakes and tending to lower their brain levels.

A 1991 study showed that the intake of aspartame in a "not unrealistically high dose" produced a "marked and persistent increase of the availability of phenylalanine to the brain".

Dr. Richard Wurtman, a neuroscientist at the Massachusetts Institute of Technology, said that while bananas, milk and NutraSweet all contain phenylalanine, one of 21 amino acids that form the "building blocks" of protein, there is more to the story. Wurtman said because aspartame lacks other important amino acids normally found in foods, the brain absorbs unusually high levels of phenylalanine that could increase the likelihood of epileptic seizures. Dr. Louis Elsas, director of medical genetics at Emory University, groans at the industry arguments that eating or drinking NutraSweet (aspartame) is just like eating a hamburger, saying that "Phenylalanine is a known toxin to the brain. Aspartame is phenylalanine, and drinking aspartame is like drinking phenylalanine as an individual amino acid."

Headache and migraine
Aspartame has been linked to headache and migraine in susceptible individuals. Dr. Walton, a professor of psychiatry at Northeastern Ohio Universities College of Medicine, states that aspartame's phenylalanine component could upset the body's balance of neurotransmitters, causing a range of neurological symptoms. Phenylalanine is a suspected migraine trigger. A University of Washington study concluded that some people are particularly susceptible to headaches caused by aspartame and may want to limit their consumption. Three randomized double-blind, placebo-controlled studies with more than 200 adult migraine sufferers showed that headaches were more frequent and more severe in the aspartame-treated group.

Depression
In 1994, a double-blind study was halted by the Institutional Review Board when eight patients with acute depression exhibited an increased expression of their symptoms after they consumed aspartame. On this basis, the authors of the study recommended that patients with unipolar depression avoid the sweetener.

Mental disorders, learning and emotional functioning
A 2008 study that looked at the direct and indirect cellular effects of aspartame on the brain proposed that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders and also in compromised learning and emotional functioning.

Acetylcholinesterase activity
Activity of the brain neurotransmitter acetylcholinesterase is markedly reduced in rats fed large amounts of aspartame. This result was replicated in human in vitro tests, and the authors concluded that "neurological symptoms, including learning and memory processes, may be related to the high or toxic concentrations of the sweetener metabolites".

Dopamine levels
Aspartame has a "relatively potent" effect in decreasing brain dopamine levels when given in very high doses to rats.

Aspartic acid
40% of aspartame by mass is broken down into aspartic acid (aspartate), an amino acid. At high concentrations, aspartate can act as an excitotoxin, inflicting damage on brain and nerve cells.

Seizures
In patients with epilepsy, excessive intake of aspartame can decrease the threshold for seizures or prolong them once they appear. However, if the intake is not above the recommended level of 40 mg/kg b.w./day, aspartame is well tolerated in this subpopulation. Aspartame appears to exacerbate the amount of EEG spike wave in children with absence seizures. Although there are reports of seizure after intake of large amounts of aspartame, intakes over 1g/day were needed to alter brain neurotransmitters and provoke seizures in monkeys.

Flight performance
In 1992, the US Air Force magazine Flying Safety published an article which expressed concerns about the effect of aspartame on pilots, and warned that some pilots who drink diet sodas containing aspartame could be more susceptible to conditions ranging from flicker vertigo to gradual loss of vision.

Movie Sweet Misery: A Poisoned World
In 2004 a movie called Sweet Misery: A Poisoned World was released and distributed through Cinema Libre Studio. Narrator Cori Brackett believes her inability to walk and speak, which faded after she stopped ingesting aspartame, show the chemical is dangerous.